Macrophages in oncoviral infections: from immune regulators to therapeutic targets.

BACKGROUND

Human oncoviruses infect host cells and drive tumorigenesis. Macrophages, as key innate immune cells, exhibit functional heterogeneity and polarization plasticity. They are broadly classified into proinflammatory M1 and anti-inflammatory M2 states, which determine their role in immunity and tissue homeostasis.

METHODS

We summarized the recent experimental and clinical studies on the interactions between macrophages and the major oncoviruses, including Epstein-Barr virus (EBV), Kaposi's Sarcoma-associated herpesvirus (KSHV), hepatitis B virus (HBV), hepatitis C virus (HCV), human T-cell leukemia virus type 1 (HTLV-1), and human papillomavirus (HPV). We focus on how viral proteins, non-coding RNAs, and extracellular vesicles reprogram macrophage functions and discuss emerging macrophage-targeted therapeutic strategies.

RESULTS

Oncoviruses drive macrophages toward pro-tumor M2 or dysfunctional M1 states by altering cytokine secretion, activating signaling pathways, such as cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and nuclear factor kappa B (NF-κB), and reprogramming metabolic pathways. New therapeutic strategies targeting macrophages, including polarization modulation, bispecific antibodies, nanomedicine delivery systems, and immune checkpoint strategies, show promise in enhancing antiviral and antitumor immunity.

CONCLUSION

Macrophages can sense various oncoviruses and play a role in oncovirus infection, chronic inflammation, and virus-driven tumorigenesis. Potential therapeutic strategies targeting macrophages offer new avenues for the precision treatment of oncovirus-associated diseases.